Increased cell death is a hallmark of neurodegenerative diseases including Alzheimer's disease (AD). The PI3K/Akt signaling pathway plays critical roles in cell survival. Its targets include components of the cell death machinery, like the BCL-2 and FOXO families, transcription factors important for cell survival, and kinases like GSK3_ involved in the generation of neurofibrillary tangles (NFT) of Alzheimer's disease. Presenilin 1 (PS1) is a transmembrane protein involved in familial Alzheimer's disease (FAD). Classic cadherins, including epithelial (E)- and neural (N)-cadherins, are major cell-cell adhesion receptors involved in the development, maintenance and function of almost all solid tissues. PS1 binds cadherins and regulates their function and processing. Using PSI+/+ and PS1 knockout (PS1-/-) fibroblasts we noticed that absence of PS1 correlates with apoptotic cell death and decreased activity of the PI3K/Akt cell survival pathway. Re-introduction of PS1 in PSI-/- cells activates the PI3K/Akt pathway and rescues cells from apoptosis suggesting that PS1 mediates transmission of survival signals. PSI-induced cell survival requires PI3K activity. These data indicate that PS1 activates the PI3K/Akt pathway. Cadherin adhesion stimulates the PI3K/Akt pathway by promoting cadherin association with the p85 subunit of PI3K. Our data show that PS1 stabilizes the cadherin/p85 association suggesting a mechanism for the PS1 cell survival effects. Furthermore, we obtained evidence that PS1 is important for insulin growth factor (IGF)-induced stimulation of the PI3K/Akt pathway, suggesting that PS1 may be involved in tyrosine kinase receptor signaling. Several PS1 FAD mutants showed a decreased ability to activate Akt or to phosphorylate GSK3[3 kinase. Here we propose to investigate the cell survival function of PS1, the mechanisms involved in the PSI-mediated activation of the PI3K/Akt pathway and the effects of PS1 FAD mutations on the activation of the PI3K/Akt pathway and on cell survival. [unreadable] [unreadable]